PURPOSE: P-glycoprotein-mediated transcellular transport of anticancer agents and the inhibitory effect of cyclosporin analogs and FK506 were investigated. METHODS: The transcellular transport of daunorubicin and vinblastine by monolayers of LLC-GA5-COL150 cells which overexpressed P-glycoprotein was measured in the presence and absence of cyclosporins or FK506. RESULTS: Cyclosporins and FK506 inhibited P-glycoprotein-mediated transport of daunorubicin and vinblastine in the order of cyclosporin D, dihydrocyclosporin D > cyclosporin A > FK506 > cyclosporin C, dihydrocyclosporin C. The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect of cyclosporin D was concentration-dependent. The inhibitory effect of the modulators on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity. CONCLUSIONS: In the transcellular transport system, lipophilicity may be one of the determinants for the inhibitory effect of various multidrug resistance modulators on the P-glycoprotein-mediated transport.
PURPOSE: P-glycoprotein-mediated transcellular transport of anticancer agents and the inhibitory effect of cyclosporin analogs and FK506 were investigated. METHODS: The transcellular transport of daunorubicin and vinblastine by monolayers of LLC-GA5-COL150 cells which overexpressed P-glycoprotein was measured in the presence and absence of cyclosporins or FK506. RESULTS:Cyclosporins and FK506 inhibited P-glycoprotein-mediated transport of daunorubicin and vinblastine in the order of cyclosporin D, dihydrocyclosporin D > cyclosporin A > FK506 > cyclosporin C, dihydrocyclosporin C. The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect of cyclosporin D was concentration-dependent. The inhibitory effect of the modulators on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity. CONCLUSIONS: In the transcellular transport system, lipophilicity may be one of the determinants for the inhibitory effect of various multidrug resistance modulators on the P-glycoprotein-mediated transport.
Authors: V F Quesniaux; M H Schreier; R M Wenger; P C Hiestand; M W Harding; M H Van Regenmortel Journal: Eur J Immunol Date: 1987-09 Impact factor: 5.532
Authors: Y Tanigawara; N Okamura; M Hirai; M Yasuhara; K Ueda; N Kioka; T Komano; R Hori Journal: J Pharmacol Exp Ther Date: 1992-11 Impact factor: 4.030
Authors: M Hirai; K Tanaka; T Shimizu; Y Tanigawara; M Yasuhara; R Hori; Y Kakehi; O Yoshida; K Ueda; T Komano Journal: J Pharmacol Exp Ther Date: 1995-10 Impact factor: 4.030